Metallic structures incorporating bioactive materials and methods for creating the same

ABSTRACT

Disclosed herein are methods to create medical devices and medical devices including bioactive composite structures. The methods include using electroless and electrophoretic deposition and codeposition methods for providing implantable medical devices coated with bioactive composite structures. In one use, the implantable medical devices of the present invention include stents with bioactive composite structures.

CROSS-REFERENCES TO RELATED APPLICATIONS

This application is a continuation-in-part of U.S. patent application Ser. No. 10/701,262, filed on Nov. 3, 2003, which is herein incorporated by reference in its entirety for all purposes.

FIELD OF THE INVENTION

The present invention relates to electroless and electrophoretic deposition and codeposition methods for providing implantable medical devices coated with bioactive composite structures. The present invention also provides methods for creating different concentrations of bioactive materials in different portions or layers of the bioactive composite structure through the use of electroless and/or electrophoretic codeposition processes.

BACKGROUND OF THE INVENTION

In many circumstances, it is beneficial for an implanted medical device to release a bioactive material into the body once the device has been implanted. Such released bioactive materials can enhance the treatment offered by the implantable medical device, facilitate recovery in the implanted area and lessen the local physiological trauma associated with the implant. Vascular stents are a type of device that has benefited from the inclusion of bioactive materials. Stents are ridged, or semi-ridged, tubular scaffoldings that are deployed within the lumen (inner tubular space) of a vessel or duct during angioplasty or related procedures intended to restore patency (openness) to vessel or duct lumens. Stents generally are left within the lumen of a vessel or duct after angioplasty or a related procedure to reduce the risks of restenosis, abrupt reclosure or re-occlusion. Including bioactive materials such as, for example and without limitation, rapamycin or paclitaxel on the surface of the implanted stent further helps to treat, prevent or inhibit restenosis, abrupt reclosure or re-occlusion (hereinafter “reclosure”).

One challenge in the field of implantable medical devices has been adhering bioactive materials to the surface of implantable devices such that the bioactive materials will be released once the device is implanted. One approach has been to include the bioactive materials in polymeric coatings. Polymeric coatings can hold bioactive materials onto the surface of implantable medical devices and release the bioactive materials via degradation of the polymer or diffusion into liquid or tissue (in this case the polymer is non-degradable). Degradable and non-degradable polymers such as polylactic acid, polyglycolic acid, and polymethylmethacrylate have been used in drug-eluting stents.

While polymeric coatings can be used to adhere bioactive materials to implanted medical devices, there are a number of problems associated with their use. First, it is difficult to predict the degradation kinetics of polymers. Consequently, it is difficult to predict how quickly a bioactive material in a polymeric coating will be released. If a drug releases from the polymeric coating too quickly or too slowly, the intended therapeutic effect may not be achieved. Second, in some cases, polymeric coatings produce pro-thrombotic and pro-inflammatory responses. These pro-thrombotic and pro-inflammatory effects lead to the necessity of prolonged antiplatelet therapies. Further, in the case of stents, these effects can exacerbate restenosis and resulting reclosure, negative effects stents are designed to prevent. Third, adherence of a polymeric coating to a substantially different substrate, such as a stent's metallic substrate, is difficult due to differing characteristics of the materials (such as differing thermal expansion properties). The difficulty in adhering the two different material types often leads to inadequate bonding between the medical device and the overlying polymeric coating which can result in the separation of the materials over time. Such separation is an exceptionally undesirable property in an implanted medical device. Fourth, it is difficult to evenly coat a medical device with a polymeric coating. The uneven coating of a medical device can lead to unequal drug delivery across different portions of the device. This drawback is especially apparent in relation to small implantable medical devices, such as stents. Due to the viscosity of polymers during coating, it is difficult to evenly coat a medical device to faithfully replicate its form. Fifth, polymeric coatings are large and bulky relative to their bioactive material storage capacity. Sixth, when delivering a bioactive material to a patient over a longer period of time, the bioactive material needs to be stabilized. Some polymeric coatings cannot provide a stable storage environment for the bioactive material, in particular when liquid, such as blood, is able to seep into the polymeric coating. Seventh, polymeric coatings, which by their nature have large pores, can protect microorganisms in the interstices of the polymeric coating, thus increasing the risk of infection. Finally, polymeric coatings remain on the medical device once the bioactive materials they contained have fully-eluted. Thus, the negative effects of the polymeric coating remain even when the bioactive materials are no longer providing continued treatment.

Sintered metallic structures can be used as an alternative to polymeric coatings. In a typical sintering process, small particles of metal are joined by an epoxy and then treated with heat and/or pressure to weld them together and to the substrate. After this process, a porous metallic structure has then been created. While effective in some instances, sintered metallic structures have relatively large pores. When a bioactive material is loaded into the pores of a sintered metallic structure, the larger pore size can cause the biologically active material to be released too quickly. As noted above, it would be desirable to have the ability to increase the bioactive material storage capacity in a bioactive composite material so that, for example, the bioactive material can be released to a patient over a long period of time.

While several alternative methods for coating stents and other implantable medical devices with bioactive materials have also been proposed, these methods also suffer from drawbacks including those resulting from processing limitations in relation to the underlying substrate or bioactive agent to be coated; inability to obtain even distribution of coatings or bioactive materials; problems with adhesion; biocompatibility issues (e.g. toxicity, or other adverse biological response); complexity of processing; size; density (and thus volume of drug that can be held and released); timing of drug release; high electrical impedance; low radiopacity; or an impact of the coating on the underlying substrate's intended function (e.g. mechanical properties, expansion characteristics, electrical surface conduction, etc.). Thus, notwithstanding certain benefits that may be provided by polymeric coatings, sintering or other alternative methods for coating implantable medical devices with bioactive materials, there is still room for improvement. Specifically, it would be beneficial if a coating process and matrix could be provided that overcomes one or more of the above-mentioned limitations.

SUMMARY OF THE INVENTION

The present invention addresses many of the drawbacks associated with previously-available methods of loading bioactive materials onto implantable medical devices by loading bioactive materials directly into a metallic layer formed on the surface of the implantable medical device. Loading bioactive materials directly into a metallic layer is advantageous for many reasons. First, the deposited metallic layer or layers, unlike polymers, are not pro-thrombotic or pro-inflammatory. Because polymers are not used to carry the bioactive materials, once the bioactive materials have eluted from the implantable medical device, only bare metal, which is not pro-thrombotic or pro-inflammatory, is left behind. Thus, no negative effects of including the bioactive materials are left behind once the bioactive materials have fully eluted. Second, when a metallic layer is deposited onto an implantable medical device that is also made from a metal, the metallic layer and underlying device do not have substantially different characteristics, so the risk of separation is diminished significantly. Third, deposition of a metallic layer in accordance with the methods of the present invention allows for an even coating of implantable medical devices regardless of their size or geometry. Fourth, harsh processing conditions that may damage bioactive materials during the coating or loading process are not required and the ability to control the percentage of bioactive materials present within or around the metallic layer can be easily controlled. Finally, the methods according to embodiments of the present invention are economical and scaleable, and are more cost-effective than other methods of forming bioactive composite structures.

Specifically, the methods of the present invention provide electroless and/or electrophoretic deposition and codeposition processes. These processes, which will be described fully below, can provide methods for varying concentrations of bioactive materials within different portions or layers of a metallic layer formed through the particular electroless and/or electrophoretic deposition or codeposition process.

In one embodiment of the methods of the present invention, the method comprises providing a first bath comprising metal ions and at least one bioactive material wherein the metal ions and bioactive material in the first bath are provided in a first ratio; contacting a substrate with the first bath, forming a portion of a bioactive composite structure with a first concentration of metal ions and bioactive material on the substrate using an electrochemical process, altering the first ratio between the metal ions and the at least one bioactive material to form a second ratio, and continuing to form the bioactive composite structure on the substrate using an electrochemical process but with a second concentration of metal ions and the at least one bioactive material.

In one embodiment of the methods of the present invention, the electrochemical process is an electroless process. In another embodiment of the methods of the present invention, the electrochemical process is an electrophoretic process. In yet another embodiment of the methods of the present invention, an electrophoretic process is followed by an electroless process.

In another embodiment of the methods of the present invention, the altering of the first ratio to form a second ratio occurs in the first bath. In another embodiment of the methods of the present invention, the altering of the first ratio to form a second ratio occurs in a second bath.

In another embodiment of the methods of the present invention, the at least one bioactive material is selected from the group described in the detailed description definition of “bioactive materials.” In another embodiment of the methods of the present invention, the at least one bioactive material is selected from the group consisting of rapamycin, paclitaxel and HMG-COA reductase inhibitors.

Another embodiment of the methods of the present invention comprises providing a first bath comprising metal ions and at least one bioactive material at a first ratio wherein both the metal ions and the at least one bioactive material comprise a positive charge, contacting a substrate with the first bath, applying a negative charge to the substrate, and forming a bioactive composite structure on the substrate using an electrochemical process.

In an embodiment of the methods of the present invention, the applying of the negative charge is continuous and the electrochemical process is an electrophoretic process. In another embodiment of the methods of the present invention, the negative charge is removed from the substrate and when the negative charge is removed from the substrate the electrochemical process changes from an electrophoretic process to an electroless process. In yet another embodiment of the methods of the present invention, the applying of the negative charge is intermittent (i.e. pulsed) and when the charge is applied to the substrate the electrochemical process is an electrophoretic process and when the charge is not applied to the substrate the electrochemical process is an electroless process.

In another embodiment of the methods of the present invention, the at least one bioactive material comprises a positive charge due to the coupling of a surfactant to the at least one bioactive material.

In an embodiment of the methods of the present invention, after the forming of a portion of the bioactive composite structure, the first ratio in the first bath is altered to form a second ratio and wherein thereafter, the forming of the bioactive composite structure is continued. In another embodiment of the methods of the present invention, after the forming of a portion of the bioactive composite structure, a second ratio in a second bath is created and the substrate is contacted with the second bath, thus continuing the formation of the bioactive composite structure.

In another embodiment of the methods of the present invention, the at least one bioactive material is selected from the group described in the detailed description definition of “bioactive materials.” In another embodiment of the methods of the present invention, the at least one bioactive material is selected from the group consisting of rapamycin, paclitaxel and HMG-COA reductase inhibitors.

The present invention also includes medical devices. In one embodiment of the medical devices of the present invention, the medical device is formed by providing a first bath comprising metal ions and at least one bioactive material wherein the metal ions and the at least one bioactive material in the first bath are provided at a first ratio, contacting a substrate with the first bath, forming a portion of the bioactive composite structure with a first concentration of metal ions and the at least one bioactive material on the substrate using an electrochemical process, altering the first ratio between the metal ions and the at least one bioactive material to form a second ratio, and continuing to form the bioactive composite structure on the substrate using an electrochemical process but with a second concentration of metal ions and the at least one bioactive material.

In one embodiment of the medical devices of the present invention, the electrochemical process is an electroless process. In another embodiment of the medical devices of the present invention, the electrochemical process is an electrophoretic process.

In an embodiment of the medical devices of the present invention, the altering of the first ratio to form a second ratio occurs in the first bath. In another embodiment of the medical devices of the present invention, the altering of the first ratio to form a second ratio occurs in a second bath.

In another embodiment of the medical devices of the present invention, the at least one bioactive material is selected from the group described in the detailed description definition of “bioactive materials.” In another embodiment of the medical devices of the present invention, the at least one bioactive material is selected from the group consisting of rapamycin, paclitaxel and HMG-CoA reductase inhibitors.

In an embodiment of the medical devices of the present invention, the medical device is formed by providing a first bath comprising metal ions and at least one bioactive material at a first ratio wherein the metal ions and the at least one bioactive material comprise a positive charge, contacting a substrate with the first bath, applying a negative charge to the substrate, and forming a bioactive composite structure on the substrate using an electrochemical process.

In another embodiment of the medical devices of the present invention, the applying of the negative charge is continuous and the electrochemical process is an electrophoretic process. In yet another embodiment of the medical devices of the present invention, the applying of the negative charge is intermittent (i.e. pulsed), and when the charge is applied to the substrate the electrochemical process is an electrophoretic process and when the charge is not applied to the substrate the electrochemical process is an electroless process.

In another embodiment of the medical devices of the present invention, the at least one bioactive material comprises a positive charge due to the coupling of a surfactant to the at least one bioactive material.

In an embodiment of the medical devices of the present invention, after a portion of the bioactive composite structure is formed, the first ratio in the first bath is altered to form a second ratio and wherein thereafter, the forming of the bioactive composite structure is continued. In another embodiment of the medical devices of the present invention, after a portion of the bioactive composite structure is formed, a second ratio in a second bath is created and the substrate is contacted with the second bath, thus continuing the formation of the bioactive composite structure.

In another embodiment of the medical devices of the present invention, the at least one bioactive material is selected from the group described in the detailed description definition of “bioactive materials.” In another embodiment of the medical devices of the present invention, the at least one bioactive material is selected from the group consisting of rapamycin, paclitaxel and HMG-COA reductase inhibitors.

In another embodiment of the medical devices of the present invention, the substrate is a stent.

DETAILED DESCRIPTION I. DEFINITIONS

Some terms that are used herein are described as follows.

The term “bioactive material(s)” as used herein refers to any organic, inorganic, or living agent that is biologically active or relevant. For example, a bioactive material can be a protein, a polypeptide, a polysaccharide (e.g. heparin), an oligosaccharide, a mono- or disaccharide, an organic compound, an organometallic compound, or an inorganic compound. It can include a living or senescent cell, bacterium, virus, or part thereof. It can include a biologically active molecule such as a hormone, a growth factor, a growth factor-producing virus, a growth factor inhibitor, a growth factor receptor, an anti-inflammatory agent, an antimetabolite, an integrin blocker, or a complete or partial functional insense or antisense gene. It can also include a man-made particle or material, which carries a biologically relevant or active material. An example is a nanoparticle comprising a core with a drug and a coating on the core. Such nanoparticles can be post-loaded into pores or co-deposited with metal ions.

Bioactive materials also can include drugs such as chemical or biological compounds that can have a therapeutic effect on a biological organism. Bioactive materials include those that are especially useful for long-term therapy such as hormonal treatment. Examples include drugs for contraception and hormone replacement therapy, and for the treatment of diseases such as osteoporosis, cancer, epilepsy, Parkinson's disease and pain. Suitable biological materials can include, without limitation, anti-inflammatory agents, anti-infective agents (e.g., antibiotics and antiviral agents), analgesics and analgesic combinations, antiasthmatic agents, anticonvulsants, antidepressants, antidiabetic agents, antineoplastics, anticancer agents, antipsychotics, and agents used for cardiovascular diseases such as anti-restenosis and anti-coagulant compounds. Exemplary drugs include, but are not limited to, antiproliferatives such as paclitaxel and rampamycin and HMG-COA reductase inhibitors such as atorvastatin, cerivastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin and simvastatin, etc.

Bioactive materials also can include precursor materials that exhibit the relevant biological activity after being metabolized, broken-down (e.g. cleaving molecular components), or otherwise processed and modified within the body. These can include such precursor materials that might otherwise be considered relatively biologically inert or otherwise not effective for a particular result related to the medical condition to be treated prior to such modification.

Combinations, blends, or other preparations of any of the foregoing examples can be made and still be considered bioactive materials within the intended meaning herein. Aspects of the present invention directed toward bioactive materials can include any or all of the foregoing examples.

The term “medical device” as used herein refers to an entity not produced in nature, which performs a function inside or on the surface of the human body. Medical devices include, but are not limited to, biomaterials, drug delivery apparatuses, vascular conduits, stents, catheters, plates, screws, spinal cages, dental implants, dental fillings, braces, artificial joints, embolic devices, ventricular assist devices, artificial hearts, heart valves, venous filters, staples, clips, sutures, prosthetic meshes, pacemakers, pacemaker leads, defibrillators, neurostimulators, neurostimulator leads, and implantable or external sensors. Medical devices are not limited by size and include micromechanical systems and nanomechanical systems which perform a function in or on the surface of the human body. Embodiments of the invention include such medical devices.

The term “substrate” as used herein refers to any physical object that can be submerged in a bath and subjected to an electroless or electrophoretic deposition or codeposition process.

The terms “implants” or “implantable” as used herein refer to a category of medical devices, which are implanted in a patient for some period of time. They can be diagnostic or therapeutic in nature, and long- or short-term.

The term “self-assembly” as used herein refers to a nanofabrication process of forming a material or coating, which proceeds spontaneously from a set of ingredients. The processes of electroless deposition or codeposition, which continues spontaneously and auto-catalytically from a set of ingredients, can also be considered a self-assembly process.

The term “stents” as used herein refers to devices that are used to maintain patency of a body lumen or interstitial tract. There are two categories of stents; those which are balloon expandable (e.g., stainless steel) and those which are self-expanding (e.g., nitinol). Stents are currently used in peripheral, coronary, and cerebrovascular vessels, the alimentary, hepatobiliary, and urologic systems, the liver parenchyma (e.g., porto-systemic shunts), and the spine (e.g., fusion cages). In the future, stents will be used in smaller vessels (currently minimum stent diameters are limited to about 2 millimeters). For example, they will be used in the interstitium to create conduits between the ventricles of the heart and coronary arteries, or between coronary arteries and coronary veins. In the eye, stents are being developed for the Canal of Schlem to treat glaucoma.

The phrase “bioactive composite structure” as used herein refers to the material overlying a substrate that results from the processes herein disclosed and includes a bioactive material. A material that results from the processes herein disclosed that does not contain a bioactive material at a particular time can be referred to as a “metallic layer” or a “composite structure.”

II. METHODS OF MANUFACTURE

Embodiments of the invention include methods of coating substrates including implantable medical devices with bioactive materials to form bioactive composite structures. In one embodiment of the methods of the present invention, an electroless codeposition process is provided. In this embodiment, the concentration of bioactive materials found in one or more electroless baths is changed during the electroless codeposition process so that different amounts of bioactive materials codeposit onto the forming metallic layer at different times. In another embodiment of the present invention, an electrophoretic codeposition process is provided. In this embodiment, a negative charge is placed onto the implantable medical device during submersion in a bath so that migration of positively-charged metal ions and positively-charged bioactive materials is enhanced. In another embodiment of the methods of the present invention, the negative charge applied to the implantable medical device during submersion in a bath is pulsed (i.e. applied intermittently) so that the electrochemical process changes along with the pulsing from an electroless to an electrophoretic process or vice versa. In another embodiment of the methods of the present invention, the concentration of bioactive materials can be changed in one or more baths during the continuous or pulsed electrophoretic or electroless/electrophoretic methods of the present invention.

A. Substrate (i.e. Implantable Medical Device) and Substrate Preparation

The substrates of the present invention can be prepared in any suitable manner prior to forming a bioactive composite structure on its surface. For example, the substrate surface can be sensitized and/or catalyzed prior to performing an electroless and/or electrophoretic deposition or codeposition process of the present invention (if the surface of the substrate is not itself autocatalytic). Metals such as tin (Sn) can be used as sensitizing agents. Many metals (e.g., nickel (Ni), cobalt (Co), copper (Cu), silver (Ag), gold (Au), palladium (Pd), platinum (Pt)) are good auto catalysts. Palladium, Pt, and Cu are examples of “universal” nucleation center-forming catalysts. In addition, many non-metals are good catalysts as well.

Before creating a composite or bioactive composite structure on the surface of a substrate of the present invention, the substrate also can be rinsed and/or pre-cleaned if desired. Any suitable rinsing or pre-cleaning liquid or gas could be used to remove impurities from the surface of the substrate before creating a composite or bioactive composite structure. Also, in some embodiments, distilled water can be used to rinse the substrate after sensitizing and/or catalyzing, but before performing the electroless and/or electrophoretic deposition or codeposition process in order to remove loosely attached molecules of the sensitizer and/or catalyst.

Prior to creating a composite or bioactive composite structure, the substrates of the present invention also can undergo an anodic process. In this process, the substrate is submerged in a hydrochloric acid bath. Current is passed through the hydrochloric acid bath, creating small pits in the substrate. Such pits promote adhesion. Also, a sensitizing agent and/or catalyst can be deposited on the substrate to assist in the creation of nucleation centers leading to the formation of the composite or bioactive composite structure. Loosely adhered nucleation centers can also be removed from the surface of the substrate using, for example, a rinsing process.

A substrate also can be immersed in a “striking” bath as described in co-pending U.S. patent application Ser. No. 10/701,262 filed on Nov. 3, 2003, which incorporated by reference herein for all it contains regarding striking baths. Specifically, in a striking bath, a current is applied across the substrate causing metal ions to move to the device and plate the surface. This step causes an intermediate or “strike” layer to be formed on the surface of the substrate. Metal ions for this first striking bath are chosen to be compatible with the material making up the substrate itself. For example, if the underlying substrate is made of cobalt chrome, cobalt ions are used. It has been found that this strike layer improves overall adherence of the coating to the substrate as well as increasing the rate of deposition or codeposition during subsequent electroless and/or electrophoretic deposition or codeposition processes. In one embodiment, when striking is performed, the substrate is rinsed with water prior to subsequent electroless and/or electrophoretic deposition or codeposition.

Substrates of the present invention also can be immersed in a bath to form a seed layer (also disclosed in co-pending U.S. patent application Ser. No. 10/701,262 filed on Nov. 3, 2003, which is incorporated by reference herein for all it contains regarding seed layers). A seed layer is an electrolessly deposited metallic layer that is deposited before bioactive material deposition. In one embodiment, a seed layer can be formed directly onto the surface of a substate. In another embodiment, a seed layer can be formed on the surface of a strike layer. Metals for this seed layer also are chosen to be compatible with the material making up the substrate itself and/or the strike layer. A seed layer can be beneficial because it also can enhance the deposition and adhesion of a subsequently deposited biocomposite structure. In one embodiment, when a seed layer is formed, the substrate is rinsed with water prior to subsequent electroless and/or electrophoretic deposition or codeposition.

B. Electrochemical Processes

After a substrate has been prepared according to any of the treatments described above, the substrate undergoes an electroless and/or electrophoretic deposition or codeposition process to create a metallic layer or metallic layer with bioactive materials on the surface of the substrate. For purposes of the following discussion, deposition refers to deposition of metal alone (although, as will be understood by one of skill in the art, an electroless or electrophoretic deposition process also involves ions of a reducing agent). Codeposition refers to deposition of metal and bioactive materials through an electroless or electrophoretic process. While the majority of methods herein disclosed include codeposition methods, deposition methods are mentioned as well because some codeposition methods of the present invention begin (or end in the case of topcoat formation (see infra)) with a stage of deposition.

In conventional electrodeposition (i.e. electroplating), an anode and cathode are electrically coupled through an electrolyte. As current passes between the electrodes, metal is deposited on the cathode while it is either dissolved from the anode or originates from the electrolyte solution. These electrodeposition processes are well known in, for example, the metal plating industry and in the electronics industry.

An exemplary reaction sequence for the reduction of metal in an electrodeposition process is as follows: M^(Z+) _(solution)+z^(e)→M_(lattice(electrode)) In this equation, M is a metal atom, M^(Z+) is a metal ion with z charge units and e is an electron (carrying a unit charge). The reaction at the cathode is a reduction reaction and is the location where electrodeposition occurs. There is also an anode where oxidation takes place. To complete the circuit, an electrolyte solution is provided. The oxidation and reduction reactions occur in separate locations in the solution. In an electrodeposition process, the substrate is a conductor as it serves as the cathode in the process. Specific electrodeposition conditions such as the current density and metal ion concentration can be determined by those of ordinary skill in the art.

As contrasted to electrodeposition, in an electroless deposition process, current does not pass through a solution. Rather, the oxidation and reduction processes both occur at the same “electrode” (i.e., on the substrate). It is for this reason that electroless deposition results in the deposition of a metal and an anodic product (e.g., nickel and nickel-phosphorus).

In an electroless deposition process, the fundamental reaction is: M^(Z+) _(solution)+R_(ed solution)→M_(lattice(catalytic surface))+Ox_(solution) In this equation, R is a reducing agent, which passes electrons to the substrate and the metal ions. Ox is the oxidized byproduct of the reaction. In an electroless process, electron transfer occurs at substrate reaction sites (initially the nucleation sites on the substrate; these then form into sites that are tens of nanometers in size). The reaction is first catalyzed by the substrate and is subsequently auto-catalyzed by the reduced metal as a metal matrix forms.

The electroless deposition bath comprises at least a reducing agent and metal ions alone or a reducing agent, metal ions and a bioactive material. The solvent that is used in the electroless deposition bath can include water so that the deposition bath is aqueous. Deposition conditions such as the pH, deposition time, bath constituents, and deposition temperature can be chosen by those of ordinary skill in the art.

During the electroless deposition processes of the present invention, metal ions deposit over the surface of the substrate. When bioactive materials are included in the solution or bath during electroless codeposition processes, without being bound by theory, it is believed that tens of nanometers of metal first deposit onto the surface of the stent. Following this deposition of tens of nanometers of metal, metal ions and bioactive materials codeposit onto the already deposited metal. Thus, the bioactive material and the metal atoms can deposit substantially simultaneously. When codepositing metal atoms and bioactive materials, the bioactive material is incorporated into the metal matrix. These crystallites confine the bioactive material in the formed bioactive composite structure.

By codepositing the bioactive material along with the metal, the concentration of the bioactive material in the bioactive composite structure can be high. Moreover, the problems associated with impregnating porous structures with bioactive materials are not present in the electroless or electrophoretic codeposition methods of the present invention.

As an example of an electroless codeposition method of the present invention, in one embodiment, a nickel-phosphorous alloy matrix can be electrolessly codeposited on a substrate along with a bioactive material such as a drug. In one embodiment, the substrate can be activated and/or catalyzed (using, e.g., Sn and/or Pd) prior to metallizing. To produce the alloy matrix, the electroless deposition bath can contain NiSO₄ (26 g/L), NaH₂PO₂ (26 g/L), Na-acetate (34 g/L) and malic acid (21 g/L). The bath can contain ions derived from the previously mentioned salts. A bioactive material is also in the bath. Non-limiting examples of bioactive materials that can be included in the presently-described bath include 1 mg paclitaxel, 1 mg rapamycin, and/or 1 mg cervistatin. In this embodiment, sodium hypophosphite is the reducing agent and nickel ions are reduced by the sodium hypophosphite. The temperature of the bath is from about room temperature to about 95° C. depending on desired codeposition time. The pH is generally from about 5 to about 7 (these processing conditions could be used in other embodiments). The substrate to be coated is then immersed in the bath and a bioactive composite structure is formed on the surface of the substrate after a predetermined amount of time. The Ni ions in solution deposit onto the surface of the substrate as pure nickel (reduction reaction) along with nickel-phosphorous alloy (oxidation reaction); the bioactive material codeposits along the crystallite and grain boundaries of the deposited metal matrix to form a bioactive composite structure. Typically, the amount of phosphorous ranges from about greater than 1% to about less than 25%. (mole %) and can be varied by techniques known to those skilled in the art.

In one embodiment of the electroless codeposition processes of the present invention, the concentration of bioactive materials in the electroless bath can be altered to vary the amount of bioactive materials codepositing, and thus found, in different portion or layers of the bioactive composite structure. In one embodiment, the concentration of bioactive materials can be changed in the same bath in which an electroless codeposition process is occurring. In another embodiment, the changed concentration of bioactive materials can occur in a second (or third, etc.) bath. In this embodiment, the substrate is removed from one bath and placed into another. These methods of varying the concentration of bioactive materials in one or more baths provide avenues to increase or decrease the amount of bioactive materials found in different portions or layers of the bioactive composite structure formed on the substrates of the present invention.

The present invention also provides electrophoretic deposition and codeposition methods. In electrophoretic deposition or codeposition methods, a slight charge is placed onto the substrate to be coated in order to attract positively-charged metal ions and positively-charged bioactive materials. The amount of charge placed onto the substrate is not, however, sufficient to change the balance of the process into an electrodeposition (or electrocodeposition) only process as described above. Thus, the reactions occurring in the bath resemble electroless processes but with a migration of positively-charged metal ions and positively-charged bioactive materials toward the slightly-charged substrate.

In one embodiment of the electrophoretic codeposition methods of the present invention, the substrate can be sensitized in 37% hydrogen chloride (HCl) for approximately 3 to 10 minutes, and in one embodiment, for approximately 5 minutes. The substrate can then be activated with an electrolytic Ni-strike. The Ni-strike can occur in, for example and without limitation, a Woods strike bath (comprising approximately 240 g/L nickel chloride and approximately 320 ml/L HCl) or a Sulfamate strike bath (comprising approximately 320 g/L nickel sulfamate; approximately 30 g/L boric acid; approximately 12 g/L HCl; and approximately 20 g/L sulfamic acid). Appropriate submersion times in these strike baths can be approximately 1-4 minutes and in one embodiment 2.5 minutes. Activation also can include application of an approximately 50-200 mAmp current, and in one embodiment, a 100 mAmp current.

After activation in a strike bath, the substrate can have a small nickel-phosphorous (Ni—P) layer created on its surface by submerging the substrate in an electroless Ni—P bath comprising approximately 35.6 g/L nickel sulfamate; approximately 17 g/L sodium hypophosphate; approximately 15 g/L sodium succinate; approximately 1.3 g/L succinic acid for approximately 2 to 10 minutes (in one embodiment 5 minutes) at approximately 30-70° C. Following the creation of this Ni—P layer, the substrate can be mounted on a masking electrode and immersed in, in a non-limiting example, an electrophoretic Ni—P-surfactant-paclitaxel solution. Submersion in this bath can occur for approximately 20 to 60 minutes (in one embodiment for 30 minutes) at approximately 30-50° C. (in one embodiment 50° C.) with a current of approximately 0.1-20 mAmp (in one embodiment 5 mAmp).

In the electrophoretic codeposition methods of the present invention, bioactive materials can be given a positive charge by coupling a surfactant to the bioactive material. Non-limiting examples of surfactants that can be used in accordance with the present invention include hexadecyl trimethyl ammonium bromide (HTAB), benzethonium chloride (BZTC) and cationic cyclodextrin complexes such as, without limitation, N,N-diethylaminoethyl-β-cyclodextrin and 2,3-Di-(N,N-diethylaminoethyl)-N-amino-2,3-deoxy-8-cyclodextrin. A suitable example of a zwitterionic surfactant that can be used in accordance with the present invention includes, without limitation 3-[(3-cholamido-propyl)-dimethyl-ammonio]-1-propanesulfonate “CHAPS”.

Dispersing agents also can be used in accordance with the present invention. Dispersing agents can prevent bioactive materials, such as, without limitation, taxol, from aggregating within a solution or bath. Anionic dispersing agents that can be used in accordance with the present invention include sodium lignosulfonate, sodium naphthalene sulfonate-formaldehyde condensate (“Lomar D”), sodium polystyrene sulfonate (Flexan 130), polyacrylic acid (Acumer 9400″ and Good-Rite k-732) and organic phosphate ester (Emphos CS-1361). Nonionic dispersing agents that can be used in accordance with the present invention include, without limitation, aliphatic alcohol ethoxylate (Atlas G5000), ethylene oxide-propylene oxide block copolymer (HLB=17.0; Pluronic P65) and polyoxyethylene (20) monolaurate (HLB=16.7; Tween 20™). Cationic dispersing agents that can be used in accordance with the present invention include, without limitation, dimethyl dicoco ammonium chloride (Arquad® 2C-75, Akzona Inc., Enka, N.C.) and N-alkyl(soya)trimethyl ammonium chloride (Arquad® S-50, Akzona Inc., Enka, N.C.). A zwitterionic dispersing agent that can be used in accordance with the present invention includes, without limitation, palmitamidopropylbetaine (Scheercotaine PAB).

Wetting agents also can be used in accordance with the present invention. Wetting agents can lower the interfacial tension between bioactive materials, such as and without limitation, taxol and water. Anionic wetting agents that can be used in accordance with the present invention include, without limitation, sodium lauryl sulfate, sodium dioctyl sulfosuccinate (“aerosol otb”), sodiumdodecyl benzene sulfonate (“witconate 90”) and sodium isopropyl naphthalene sulfonate (“aerosol OS”). Nonionic wetting agents that can be used in accordance with the present invention include, without limitation, secondary alcohol ethoxylate (tergitolo 15-5-5; Union Carbide Chemicals & Plastics Technology Corp., Danbury, Conn.) and Pluronic L-62 (a block copolymer of propylene oxide and ethylene oxide).

In one embodiment of the methods of the present invention, after a portion of a biocomposite structure has formed, the negative charge applied to the substrate can be removed to change the process from an electrophoretic process to an electroless process. Changing the electrochemical process from an electrophoretic process to an electroless process can be desirable to alter the concentration of bioactive materials found in different layers of the biocomposite structure. For example, an electrophoretic process generally results in a higher concentration of bioactive material deposition than an electroless process. Performing an electrophoretic process first results in a higher concentration of bioactive materials closer to the surface of the substrate. These bioactive materials can release through a second electroless layer. This codeposition and release procedure results in an extended and sustained release of bioactive materials from the electrophoretic layer through the second electroless layer. A lower concentration of bioactive materials found in the second electroless layer can be released more quickly for short term release needs.

In another embodiment of the methods of the present invention, the current applied to the substrate during the electrophoretic processes can be pulsed on and off, changing the process in an on-going manner from an electrophoretic to an electroless deposition or codeposition process. In one embodiment of the “pulsing” embodiments of the present invention, the current can be pulsed on and off in approximately 1 to 10 second intervals for approximately 10 to 60 seconds at a time. In another embodiment of the present invention, phosphorous content is manipulated through pulsing so that, within a particular bioactive composite structure formed, phosphorous content is high only at the surface of the structure, providing enhanced resistance to corrosion without increasing the overall brittleness of the bioactive composite structure.

Any suitable source of metal ions can be used in embodiments of the invention. The metal ions in a particular bath can be derived from soluble metal salts before they are in the bath. In solution, the ions forming the metal salts can dissociate from each other. Non-limiting examples of suitable metal salts for nickel ions include nickel sulfate, nickel chloride, and nickel sulfamate. Non-limiting examples of suitable metal salts for cobalt ions include cobalt sulfate, cobalt chloride, and cobalt sulfamate. Non-limiting examples of suitable metal salts for copper ions include cupric and cuprous salts such as cuprous chloride or sulfate. Non-limiting examples of suitable metal salts for tin cations can include stannous chloride or stannous fluoroborate. Other suitable salts useful for depositing other metals are known in the electroless deposition art. Different types of salts can be used if a metal alloy matrix is to be formed.

The bath also can include a reducing agent, complexing agents, stabilizers, and buffers. The reducing agent reduces the oxidation state of the metal ions in solution so that the metal ions deposit on the surface of the substrate as metal. Non-limiting examples of reducing compounds include boron compounds such as amine borane and phosphites such as sodium hypophosphite. Complexing agents are used to hold the metal in solution. Buffers and stabilizers are used to increase bath life and improve the stability of the bath. Buffers are used to control the pH of the bath. Stabilizers can be used to keep the solution homogeneous. Non-limiting examples of stabilizers include lead, cadmium, copper ions, etc. Reducers, complexing agents, stabilizers and buffers are well known in the electroless deposition art and can be chosen by those of ordinary skill in the art.

The metallic matrix of the bioactive composite structure formed during the electroless or electrophoretic deposition or codeposition methods of the present invention can include any suitable metal. The metal in the metallic matrix can be the same as or different from the substrate metal (if the substrate is metallic). The metallic matrix can include, for example, noble metals or transition metals. Suitable metals include, but are not limited to, nickel, copper, cobalt, palladium, platinum, chromium, iron, gold, and silver and alloys thereof. Examples of suitable nickel-based alloys include, without limitation, Ni—P, nickel-boron (Ni—B) and nickel chromium (Ni—Cr). Any of these or other metallic materials can be deposited using a suitable electroless or electrophoretic deposition or codeposition process. Appropriate metal salts can be selected to provide appropriate metal ions in the bath for the metal matrix that is to be formed.

After a substrate has contacted the baths of the present invention and undergone an electroless or electrophoretic codeposition process, a bioactive composite structure has been formed on the substrate's surface. After this bioactive composite structure has been formed, the structure/substrate combination can be subjected to subsequent processing as desired.

C. Subsequent Processing

After electroless or electrophoretic codeposition onto the surface of the substrate, the device can be processed further to alter its clinical features. In one embodiment, this processing can include formation of a top coat. This topcoat can include any suitable material and can be in any suitable form. It can be amorphous or crystalline, and can include a metal, ceramic, etc. The topcoat can also be porous or solid (continuous).

The topcoat can be deposited using any suitable process. For example, the above-described processes (e.g., electrodeposition or codeposition or electroless or electrophoretic deposition or codeposition) could be used to form the topcoat or another process can be used to form the topcoat. Alternatively, the topcoat could be formed by processes such as, but not limited to, dip coating, spray coating, vapor deposition, etc.

In some embodiments, the topcoat can improve the properties of the bioactive composite structure. For example, the topcoat can include a membrane (e.g., collagen type 4) that is covalently bound to the bioactive composite structure. The topcoat's function can be to induce endothelial attachment to the surface of a bioactive composite structure, while the bioactive material in the bioactive composite structure diffuses from below the topcoat. In another embodiment, a growth factor such as endothelial growth factor (EGF) or vascular endothelial growth factor (VEGF) is present in a topcoat that is on a bioactive composite structure. The growth factor is released from the topcoat to induce endothelial growth while the bioactive composite structure releases an inhibitor of smooth muscle cell growth.

In yet another embodiment of the present invention, the topcoat can improve the radioopacity of a medical device which includes the bioactive composite structure, while the underlying bioactive composite structure releases molecules to perform another function. For example, drugs can be released from the bioactive composite structure to prevent smooth muscle cell overgrowth, while a topcoat on the bioactive composite structure improves the radioopacity of the formed medical device. Illustratively, a topcoat comprising, for example and without limitation, nickel, cobalt, Ni—Cr and/or gold can be deposited on top of a bioactive composite structure comprising Ni—P to enhance the radioopacity of a device incorporating the bioactive composite structure. Underneath the topcoat, a smooth muscle cell inhibitor such as sirolimus can be released over a 30-60 day time period from the bioactive composite structure.

The topcoat can also be used to alter the release kinetics of the bioactive material in the underlying bioactive composite structure. For example, an electroless nickel-phosphorous or cobalt-phosphorous coating without bioactive material can serve as a topcoat. This would require the bioactive material to travel through an additional layer of material before entering the surrounding environment, thereby delaying the release of the bioactive material. The release kinetics of the formed medical device can be adjusted in this manner.

Although medical devices such as stents are discussed in detail, it is understood that embodiments of the invention are not limited to stents or for that matter, to macroscopic devices. For example, embodiments of the invention could be used in any device or material, regardless of size and includes artificial hearts, plates, screws, mems (microelectromechanical systems), and nanoparticle based materials and systems, etc. Further, the substrate can be porous or solid, flexible or rigid, and can have a planar or non-planar surface (e.g., curved).

The terms and expressions which have been employed herein are used as terms of description and not of limitation, and there is no intention in the use of such terms and expressions of excluding equivalents of the features shown and described, or portions thereof, it being recognized that various modifications are possible within the scope of the invention claimed. Moreover, any one or more features of any embodiment of the invention can be combined with any one or more other features of any other embodiment of the invention, without departing from the scope of the invention.

Unless otherwise indicated, all numbers expressing quantities of ingredients, properties such as molecular weight, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term “about.” Accordingly, unless indicated to the contrary, the numerical parameters set forth in the following specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained by the present invention. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as possible. Any numerical value, however, inherently contains certain errors necessarily resulting from the standard deviation found in their respective testing measurements.

The terms “a” and “an” and “the” and similar referents used in the context of describing the invention (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. Recitation of ranges of values herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range. Unless otherwise indicated herein, each individual value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g. “such as”) provided herein is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention otherwise claimed. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the invention.

Groupings of alternative elements or embodiments of the invention disclosed herein are not to be construed as limitations. Each group member may be referred to and claimed individually or in any combination with other members of the group or other elements found herein. It is anticipated that one or more members of a group may be included in, or deleted from, a group for reasons of convenience and/or patentability. When any such inclusion or deletion occurs, the specification is herein deemed to contain the group as modified thus fulfilling the written description of all Markush groups used in the appended claims.

Preferred embodiments of this invention are described herein, including the best mode known to the inventors for carrying out the invention. Of course, variations on those preferred embodiments will become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventor expects skilled artisans to employ such variations as appropriate, and the inventors intend for the invention to be practiced otherwise than specifically described herein. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context.

Furthermore, numerous references have been made to patents and printed publications throughout this specification. Each of the above cited references and printed publications are herein individually incorporated by reference in their entirety.

In closing, it is to be understood that the embodiments of the invention disclosed herein are illustrative of the principles of the present invention. Other modifications that may be employed are within the scope of the invention. Thus, by way of example, but not of limitation, alternative configurations of the present invention may be utilized in accordance with the teachings herein. Accordingly, the present invention is not limited to that precisely as shown and described. 

1. A method comprising: providing a first bath comprising metal ions and at least one bioactive material wherein said metal ions and said at least one bioactive material in said first bath are provided at a first ratio; contacting a substrate with said first bath; forming a bioactive composite structure with a first concentration of metal ions and said at least one bioactive material on said substrate using an electrochemical process; altering said first ratio between said metal ions and said at least one bioactive material to form a second ratio; continuing to form said bioactive composite structure on said substrate using an electrochemical process but with a second concentration of metal ions and said at least one bioactive material.
 2. The method according to claim 1, wherein said electrochemical process is an electroless process or an electrophoretic process.
 3. The method according to claim 1, wherein said altering of said first ratio to form said second ratio occurs in said first bath.
 4. The method according to claim 1, wherein said altering of said first ratio to form said second ratio occurs in a second bath.
 5. A method comprising: providing a first bath comprising metal ions and at least one bioactive material at a first ratio wherein said metal ions and said at least one bioactive material comprise a positive charge; contacting a substrate with said first bath; applying a negative charge to said substrate; forming a bioactive composite structure on said substrate using an electrochemical process.
 6. The method according to claim 5, wherein said applying of said negative charge is continuous and said electrochemical process is an electrophoretic process.
 7. The method according to claim 5, wherein said method further comprises removing said negative charge from said substrate and continuing to form said bioactive composite structure through an electroless process.
 8. The method according to claim 5, wherein said applying of said negative charge is intermittent and wherein when said charge is applied to said substrate said electrochemical process is an electrophoretic process and wherein when said charge is not applied to said substrate said electrochemical process is an electroless process.
 9. The method according to claim 5, wherein said at least one bioactive material comprises a positive charge due to the coupling of a surfactant to said at least one bioactive material.
 10. The method according to claim 5, wherein after said forming of a portion of said bioactive composite structure, said first ratio in said first bath is altered to form a second ratio and wherein thereafter, said forming of said bioactive composite structure is continued.
 11. The method according to claim 5, wherein after said forming of a portion of said bioactive composite structure, a second ratio in a second bath is created and wherein said substrate is contacted with said second bath, thus continuing the formation of said bioactive composite structure.
 12. A medical device formed by a method comprising: providing a first bath comprising metal ions and at least one bioactive material wherein said metal ions and said at least one bioactive material in said first bath are provided at a first ratio; contacting a substrate with said first bath; forming a portion of a bioactive composite structure with a first concentration of metal ions and said at least one bioactive material on said substrate using an electrochemical process; altering said first ratio between said metal ions and said at least one bioactive material to form a second ratio; and continuing to form said bioactive composite structure on said substrate using an electrochemical process but with a second concentration of metal ions and said at least one bioactive material.
 13. The medical device according to claim 12, wherein said electrochemical process is an electroless process or an electrophoretic process.
 14. The medical device according to claim 12, wherein said altering of said first ratio to form said second ratio occurs in said first bath.
 15. The medical device according to claim 12, wherein said altering of said first ratio to form said second ratio occurs in a second bath.
 16. A medical device formed by a method comprising: providing a first bath comprising metal ions and at least one bioactive material at a first ratio wherein said metal ions and said at least one bioactive material comprise a positive charge; contacting a substrate with said first bath; applying a negative charge to said substrate; forming a bioactive composite structure on said substrate using an electrochemical process.
 17. The medical device according to claim 16, wherein said applying of said negative charge is continuous and said electrochemical process is an electrophoretic process.
 18. The medical device according to claim 16, wherein said applying of said negative charge is intermittent and wherein when said charge is applied to said substrate said electrochemical process is an electrophoretic process and when said charge is not applied to said substrate said electrochemical process is an electroless process.
 19. The medical device according to claim 16, wherein said at least one bioactive material comprises a positive charge due to the coupling of a surfactant to said at least one bioactive material.
 20. The medical device according to claim 16, wherein after said forming of a portion of said bioactive composite structure, said first ratio in said first bath is altered to form a second ratio and wherein thereafter, said forming of said bioactive composite structure is continued.
 21. The medical device according to claim 16, wherein after said forming of a portion of said bioactive composite structure, a second ratio in said second bath is created and wherein said substrate is contacted with said second bath, thus continuing the formation of said bioactive composite structure.
 22. The medical device according to claim 16, wherein said substrate is a stent. 